The synthesis of water-dispersible derivatives of cellulose has long been a difficult problem, of significant commercial and scientific importance. Practical synthesis of water-soluble cellulose derivatives is possible, for example by acylation followed by extensive back-hydrolysis (Buchanan et al., Macromolecules 1991, 24, 3050-3059), or by reaction of cellulose with various alkylating agents under base catalysis, to make derivatives like methylcellulose, carboxymethylcellulose (Heinze and Koschella, Macromol. Symp. 2005, 223, 13-39), hydroxyethylcellulose (Arisz et al., Cellulose 1996, 3, 45-61), or ethylcellulose (Koschella et al., Polymer Bulletin 2006, 57, 33-41). For many applications, water-dispersability is far more desirable than water solubility. For example, in coatings applications, the low viscosity of aqueous dispersions permits the formulation of high-solids coatings, minimizing things like drying time and transportation costs. One of the most straightforward ways to make an aqueous dispersion that can then coalesce into a film is to incorporate carboxyl groups into the molecule; these can be deprotonated by volatile amines, enhancing the dispersability of the polymer. Upon drying, the amine evaporates, promoting the formation of a continuous film. Polymers that are fundamentally hydrophobic, but contain carboxyl groups that enable swelling or dissolution at neutral pH, are also highly useful for drug delivery applications (U.S. Pat. No. 5,994,530). Unfortunately, there are a limited number of methods available to synthesize carboxyl-containing polysaccharides, and particularly carboxyl-containing cellulose derivatives.
The most well known synthesis of carboxyl-containing cellulose derivatives is that of carboxymethylcellulose, noted above. Typically cellulose is reacted with chloroacetic acid in water in the presence of sodium hydroxide as base. Conversion of carboxymethylcellulose into hydrophobic ester derivatives like acetate, propionate and butyrate has been reported (U.S. Pat. Nos. 5,668,273 and 5,792,856). While the resulting carboxymethylcellulose esters are very interesting materials for coatings and drug delivery applications (U.S. Pat. No. 5,994,530), there must be concern with acid-catalyzed esterification of a polymer which contains both carboxyl and hydroxyl groups; cross-linking by esterification is always a possibility. Another method is the reaction of cellulose or a cellulose derivative with a cyclic anhydride, usually with a basic catalyst like pyridine or triethylamine. In that way, syntheses of carboxyl-substituted derivatives of cellulose such as cellulose acetate phthalate (U.S. Pat. No. 5,925,181) and cellulose acetate butyrate succinate (U.S. Pat. No. 5,888,550) have been reported. The known carboxyl-substituted cellulose derivatives prepared by this cyclic anhydride ring-opening chemistry suffer from limited stability in aqueous systems, which is of course a drawback for polymers designed for aqueous dispersions. The stability of cellulose acetate butyrate succinate, for example, is limited (Edgar, Polymers Paint Colour J. 1993, 183, 564-571). The author of that study speculated that the particular instability of derivatives like succinate arises from their ability to autocatalyze their hydrolysis (Scheme 1).

Cellulose adipate derivatives might be superior to the cellulose phthalates and succinates synthesized in earlier work. They should not be prone to autocatalyzed hydrolysis, since that would require an unfavorable 7-membered ring transition state (Scheme 2). They will be more hydrophobic than the corresponding succinate or phthalate derivatives, and thus would be expected to be more compatible with hydrophobic drugs. Unfortunately, there are no reports of the synthesis of cellulose adipates. Lignocellulosic materials have been subjected to surface treatments with adipic acid in order to crosslink and strengthen those materials (Seidel et al., Starch 2001, 53, 305-310; Coma et al., Carb. Polymers 2003, 51, 265-271), but the products were poorly characterized and certainly no discrete cellulose derivatives were claimed or described.

Adipic anhydride would be the directly analogous reagent to consider for ring-opening reaction with cellulose to produce cellulose adipates. Adipic anhydride is highly reactive due to its relatively strained 7-membered ring structure. It is prone to homopolymerization, and has most commonly been used to synthesize polyanhydrides (Morello et al., Microencapsulation 2007, 24, 40-56) and polyesters (Carnahan et al., Macromolecules 2006, 39, 609-616).
Therefore, there remains a need for a method of making esters of diacids and cellulosic materials.